Feature Articles

Innovative Drug Screening Methodologies

New Assays Streamline Scrutiny of Cellular and Molecular Binding Events

Stem Cell Hemotoxicity

According to Ivan N. Rich, Ph.D., founder, chairman, and CEO at HemoGenix, conventional hemotoxicity evaluation is not an accurate predictive tool during preclinical animal testing.

The colony-forming assay was developed over 40 years ago as an in vitro means of testing cellular response of blood-forming cells to various agents. Cells are plated in petri dishes in a special medium containing methyl cellulose to immobilize them, and the number of colonies per cell plated can be measured as a function of the treatment. But the procedure suffers from a number of shortcomings, including subjectivity, long incubation periods, and a low-throughput performance.

For this reason, Dr. Rich and his colleagues have investigated the possibilities of using hemopoietic stem cells for a more meaningful and functional assay. These cells have the capacity to produce a number of lineages of mature functional cells, and offer the promise of a well-delineated model for testing of toxic compounds.

The company offers a variety of kits for measuring proliferation and cytotoxicity using its HALO®, ATP bioluminescence, and differentiation assays. This procedure has been validated against the Registry of Cytotoxicity Prediction Model, an information resource containing 347 compounds for which the LD50 and IC50 values are known.

HALO was designed for both 96- and 384-well screening to predict human in vitro hemotoxicity. The IC50 values obtained through the HALO assay correlate extremely well across a 5 log interval with cytotoxicity values generated for the registry, Dr. Rich said. The global response of drugs and other agents can be compared on seven different lympho-hematopoietic cell populations from various species.

In order to test drug-drug interactions with the HALO platform, the company has developed a 384-well plate high-throughput screening assay.

With this new assay, Dr. Rich and his colleagues have evaluated Verapamil, a p450 inhibitor, in the presence of cyclosporine. Verapamil may prevent cyclosporine from being broken down in the digestive system and the liver, leading to an increase in cyclosporine levels. These interactive patterns between the two compounds can be replicated in vitro using the HALO assay.

“The HALO assay is one of the most predictive toxicity screening tools available,” added Dr. Rich, “and combined with our other ATP-based assays allows ranking according to compound IC values, tissue, and species.”

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